This proposal will study the innate and adaptive leukocyte networks in distinct mucosal tissues of macaques to ascertain if these responses are uniquely influenced by mucosal pathogens and how they contribute to the control of immunodeficiency virus infection. The hypothesis is that there will be more robust broad-acting innate and adaptive effector responses in the oral tissues compared to the vaginal/cervical or rectal tissues upon virulent pathogen challenge and that these will be modulated by immunodeficiency virus infection. Effective innate and adaptive responses in the oral tissues will be driven largely by IFN-a and defensins released by dendritic cells (DCs) in response to the pathogens. In addition to their anti-viral properties, defensins encourage DC and T cell recruitment and IFN-a drives DC activation to promote the induction of strong effector T and B cell responses. In contrast, poor innate responses in genital/rectal tissues will limit DC activation resulting in virus-induced regulatory T cell (Treg) responses, thereby encouraging infection. Using the rhesus macaque system, three major questions will be tackled to address this hypothesis: 1 - What are the innate and adaptive responses in healthy oral, vaginal/cervical, and rectal tissues? 2 - Are the innate or adaptive mucosal responses altered by chronic immunodeficiency virus infection? 3 - How do the mucosal innate and adaptive networks respond during acute mucosal infection? By tapping into existing macaque studies we will have access to naive as well as healthy immunodeficiency virus-infected animals to dissect the basic biology of the immune responses in the different mucosal sites in healthy vs chronically infected settings (potentially into advanced disease). Additionally, we plan to commence studies involving infection of animals with immunodeficiency viruses via the vaginal and tonsillar mucosae as well as HSV-2 infection via the vaginal route. Access to these animals will provide the first insights into the innate and adaptive responses at different mucosal sites during acute viral infections. This will reveal whether differences in innate (IFN-a, defensins) and adaptive (effector vs regulatory T cells) capacities influence infection of the different mucosae and the oral manifestations associated with immunodeficiency virus infection.